Patients with hematologic malignancies can be treated with allogeneic hematopoietic stem cell transplantation (HCT). In the United States, for example, allogeneic HCT transplants have risen steadily over the past 35 years, with approximately 8,000 transplants per year since 2013 (see CIBMTR 2016 Summary). However, relapse of the hematologic malignancy can occur thereafter. Currently, a significant number of patients who receive HCT for the treatment of acute leukemia relapse (approximately 2,000 patients relapse post-HCT each year in the U.S. alone, or about 25 to 50%; see Sucheston-Campbell et al., Curr. Hematol. Malig. Rep. 10:45-58, 2015). Relapse rates are especially high in patients who are not able to achieve deep complete remissions and/or are unable to tolerate intensive conditioning regimens prior to HCT. The prognosis for patients with post-HCT relapse is abysmal: two year survival rates for patients relapsing at <100, 100-200 and >200 days after HCT are 3%, 9% and 19%, respectively. Patients who receive a second HCT may have better outcomes, but to be eligible for a second HCT, the patient must first achieve remission, which typically only occurs in about 30% of patients.
Acute leukemia relapses can, in some cases, be treated with donor lymphocyte infusions from the original stem cell donor. This graft-versus-leukemia (GVL) effect of donor lymphocyte infusion, however, is often accompanied by graft-versus-host disease (GVHD), causing serious mortality and morbidity and is not always effective. If GVL could be selectively increased without enhancing immune responses against normal tissues (graft-versus-host disease, GVHD), post-HCT relapses might be prevented.
Certain minor H antigens are expressed on leukemic stem cells and blasts (see, e.g., Bleakley and Riddell, Nat. Rev. Cancer 4:371-380, 2004; Bleakley et al., Blood 115:4923-4933, 2010; Bleakley and Riddell, Immunol. Cell. Biol. 89:396-407, 2011; van der Harst et al., Blood 83:1060-1066, 1994; Bonnet et al., Proc. Natl. Acad. Sci. USA 96:8639-8644, 1999; Hambach et al., Leukemia 20:371-374, 2006), and have been targeted using cancer-specific T cells. In a small clinical trial of minor H antigen-targeted T cell immunotherapy in patients with post-HCT relapse, clinical responses were observed in some patients (Warren et al., Blood 115:3869-3878, 2010). Technical advances in genetic modification of T cells and growing knowledge of T cell biology means that therapeutic doses of antigen-specific T cells can now be prepared efficiently, given to patients, and persist and exert potent anti-tumor effects in vivo (Heemskerk et al., J. Exp. Med. 199:885-894, 2004; Morgan et al., Science 314:126-129, 2006; Griffioen et al., Haematologica 93:1535-131543, 2008; Ochi et al., J. Biomed. Biotechnol. 2010:5212248, 2010; Schmitt et al., Hum. Gene Ther. 20:1240-1248, 2009; Stromnes et al., Immunol Rev. 257:145-164, 2014). However, there is a need for cell-based therapies that target leukemia-associated antigens. Presently disclosed embodiments address these needs and provide other related advantages.